Other 4-Methanolquinolines, Amyl Alcohols and Phentathrenes: Mefloquine, Lumefantrine and Halofantrine

  • Francois NostenEmail author
  • Penelope A. Phillips-Howard
  • Feiko O. ter Kuile
Part of the Milestones in Drug Therapy book series (MDT)


This chapter describes mefloquine, pyronaridine, halofantrine, piperaquine and lumefantrine under the broader title of the 4-methanolquinolines, amyl alcohols and phentathrenes. We provide a brief resume of each drug, in terms of their chemical properties, formulae, pharmacokinetics, clinical indications for use, and their efficacy and safety. Recognizing the limited number of antimalarials available, and in the developmental pipeline, attention is focussed on describing the history of each drug and how their indications have evolved as data on safety in human populations accumulates over time, and how patterns of use have changed with growing multiple drug resistance. Their combined use with the artemisinin derivatives is briefly described and readers are recommended to consult other chapters in this book which more fully describe such combinations.


Amyl Alcohol Artemisinin Derivative Food Vacuole Malaria Chemoprophylaxis Pfmdr1 Copy Number 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Olliaro P (2001) Mode of action and mechanisms of resistance for antimalarial drugs. Pharmacol Ther 89:207–219PubMedCrossRefGoogle Scholar
  2. 2.
    Hoppe HC, van Schalkwyk DA, Wiehart UI, Meredith SA, Egan J, Weber BW (2004) Antimalarial quinolines and artemisinin inhibit endocytosis in Plasmodium falciparum. Antimicrob Agents Chemother 48:2370–2378PubMedCrossRefGoogle Scholar
  3. 3.
    Sweeney TR (1981) The present status of malaria chemotherapy: mefloquine, a novel antimalarial. Med Res Rev 1:281–301PubMedCrossRefGoogle Scholar
  4. 4.
    Karle JM, Olmeda R, Gerena L, Milhous WK (1993) Plasmodium falciparum: role of absolute stereochemistry in the antimalarial activity of synthetic amino alcohol antimalarial agents. Exp Parasitol 76:345–351PubMedCrossRefGoogle Scholar
  5. 5.
    Brocks DR, Mehvar R (2003) Stereoselectivity in the pharmacodynamics and pharmacokinetics of the chiral antimalarial drugs. Clin Pharmacokinet 42:1359–1382PubMedCrossRefGoogle Scholar
  6. 6.
    Simpson JA, Price R, ter Kuile F, Teja-Isavatharm P, Nosten F, Chongsuphajaisiddhi T, Looareesuwan S, Aarons L, White NJ (1999) Population pharmacokinetics of mefloquine in patients with acute falciparum malaria. Clin Pharmacol Ther 66:472–484PubMedCrossRefGoogle Scholar
  7. 7.
    Gimenez F, Pennie RA, Koren G, Crevoisier C, Wainer IW, Farinotti R (1994) Stereoselective pharmacokinetics of mefloquine in healthy Caucasians after multiple doses. J Pharm Sci 83:824–827PubMedCrossRefGoogle Scholar
  8. 8.
    Martin C, Gimenez F, Bangchang KN, Karbwang J, Wainer IW, Farinotti R (1994) Whole blood concentrations of mefloquine enantiomers in healthy Thai volunteers. Eur J Clin Pharmacol 47:85–87PubMedCrossRefGoogle Scholar
  9. 9.
    Hellgren U, Jastrebova J, Jerling M, Krysen B, Bergqvist Y (1996) Comparison between concentrations of racemic mefloquine, its separate enantiomers and the carboxylic acid metabolite in whole blood serum and plasma. Eur J Clin Pharmacol 51:171–173PubMedCrossRefGoogle Scholar
  10. 10.
    Bourahla A, Martin C, Gimenez F, Singhasivanon V, Attanath P, Sabchearon A, Chongsuphajaisiddhi T, Farinotti R (1996) Stereoselective pharmacokinetics of mefloquine in young children. Eur J Clin Pharmacol 50:241–244PubMedCrossRefGoogle Scholar
  11. 11.
    Kerb R, Fux R, Morike K, Kremsner PG, Gil JP, Gleiter CH, Schwab M (2009) Pharmacogenetics of antimalarial drugs: effect on metabolism and transport. Lancet Infect Dis 9:760–774PubMedCrossRefGoogle Scholar
  12. 12.
    Svensson US, Alin H, Karlsson MO, Bergqvist Y, Ashton M (2002) Population pharmacokinetic and pharmacodynamic modelling of artemisinin and mefloquine enantiomers in patients with falciparum malaria. Eur J Clin Pharmacol 58:339–351PubMedCrossRefGoogle Scholar
  13. 13.
    Phillips-Howard PA, Steffen R, Kerr L, Vanhauwere B, Schildknecht J, Fuchs E, Edwards R (1998) Safety of mefloquine and other antimalarial agents in the first trimester of pregnancy. J Travel Med 5:121–126PubMedCrossRefGoogle Scholar
  14. 14.
    Nosten F, Vincenti M, Simpson J, Yei P, Thwai KL, de Vries A, Chongsuphajaisiddhi T, White NJ (1999) The effects of mefloquine treatment in pregnancy. Clin Infect Dis 28:808–815PubMedCrossRefGoogle Scholar
  15. 15.
    Steketee RW, Wirima JJ, Slutsker L, Roberts JM, Khoromana CO, Heymann DL, Breman JG (1996) Malaria parasite infection during pregnancy and at delivery in mother, placenta, and newborn: efficacy of chloroquine and mefloquine in rural Malawi. Am J Trop Med Hyg 55(1 Suppl):24–32PubMedGoogle Scholar
  16. 16.
    Gosling RD, Gesase S, Mosha JF, Carneiro I, Hashim R, Lemnge M, Mosha FW, Greenwood B, Chandramohan D (2009) Protective efficacy and safety of three antimalarial regimens for intermittent preventive treatment for malaria in infants: a randomised, double-blind, placebo-controlled trial. Lancet 374:1521–1532PubMedCrossRefGoogle Scholar
  17. 17.
    Briand V, Bottero J, Noel H, Masse V, Cordel H, Guerra J, Kossou H, Fayomi B, Ayemonna P, Fievet N et al (2009) Intermittent treatment for the prevention of malaria during pregnancy in Benin: a randomized, open-label equivalence trial comparing sulfadoxine-pyrimethamine with mefloquine. J Infect Dis 200:991–1001PubMedCrossRefGoogle Scholar
  18. 18.
    Nosten F, ter Kuile F, Chongsuphajaisiddhi T, Luxemburger C, Webster HK, Edstein M, Phaipun L, Thew KL, White NJ (1991) Mefloquine-resistant falciparum malaria on the Thai-Burmese border. Lancet 337:1140–1143PubMedCrossRefGoogle Scholar
  19. 19.
    Nosten F, Price RN (1995) New antimalarials. A risk-benefit analysis. Drug Saf 12:264–273PubMedCrossRefGoogle Scholar
  20. 20.
    White NJ (1992) Antimalarial drug resistance: the pace quickens. J Antimicrob Chemother 30:571–585PubMedCrossRefGoogle Scholar
  21. 21.
    ter Kuile FO, Nosten F, Thieren M, Luxemburger C, Edstein MD, Chongsuphajaisiddhi T, Phaipun L, Webster HK, White NJ (1992) High-dose mefloquine in the treatment of multidrug-resistant falciparum malaria. J Infect Dis 166:1393–1400PubMedCrossRefGoogle Scholar
  22. 22.
    Fontanet AL, Johnston DB, Walker AM, Rooney W, Thimasarn K, Sturchler D, Macdonald M, Hours M, Wirth DF (1993) High prevalence of mefloquine-resistant falciparum malaria in eastern Thailand. Bull World Health Organ 71:377–383PubMedGoogle Scholar
  23. 23.
    Fontanet AL, Johnston BD, Walker AM, Bergqvist Y, Hellgren U, Rooney W (1994) Falciparum malaria in eastern Thailand: a randomized trial of the efficacy of a single dose of mefloquine. Bull World Health Organ 72:73–78PubMedGoogle Scholar
  24. 24.
    ter Kuile FO, Nosten F, Luxemburger C, Kyle D, Teja-Isavatharm P, Phaipun L, Price R, Chongsuphajaisiddhi T, White NJ (1995) Mefloquine treatment of acute falciparum malaria: a prospective study of non-serious adverse effects in 3673 patients. Bull World Health Organ 73:631–642PubMedGoogle Scholar
  25. 25.
    Ter Kuile FO, Teja-Isavatharm P, Edstein MD, Keeratithakul D, Dolan G, Nosten F, Phaipun L, Webster HK, White NJ (1994) Comparison of capillary whole blood, venous whole blood, and plasma concentrations of mefloquine, halofantrine, and desbutyl-halofantrine measured by high-performance liquid chromatography. Am J Trop Med Hyg 51:778–784PubMedGoogle Scholar
  26. 26.
    Nosten F, van Vugt M, Price R, Luxemburger C, Thway KL, Brockman A, McGready R, ter Kuile F, Looareesuwan S, White NJ (2000) Effects of artesunate-mefloquine combination on incidence of Plasmodium falciparum malaria and mefloquine resistance in western Thailand: a prospective study. Lancet 356:297–302PubMedCrossRefGoogle Scholar
  27. 27.
    Carrara VI, Sirilak S, Thonglairuam J, Rojanawatsirivet C, Proux S, Gilbos V, Brockman A, Ashley EA, McGready R, Krudsood S et al (2006) Deployment of early diagnosis and mefloquine-artesunate treatment of falciparum malaria in Thailand: the Tak Malaria Initiative. PLoS Med 3:e183PubMedCrossRefGoogle Scholar
  28. 28.
    Carrara VI, Zwang J, Ashley EA, Price RN, Stepniewska K, Barends M, Brockman A, Anderson T, McGready R, Phaiphun L et al (2009) Changes in the treatment responses to artesunate-mefloquine on the northwestern border of Thailand during 13 years of continuous deployment. PLoS One 4:e4551PubMedCrossRefGoogle Scholar
  29. 29.
    Price R, Robinson G, Brockman A, Cowman A, Krishna S (1997) Assessment of pfmdr 1 gene copy number by tandem competitive polymerase chain reaction. Mol Biochem Parasitol 85:161–169PubMedCrossRefGoogle Scholar
  30. 30.
    Price RN, Uhlemann AC, Brockman A, McGready R, Ashley E, Phaipun L, Patel R, Laing K, Looareesuwan S, White NJ et al (2004) Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet 364:438–447PubMedCrossRefGoogle Scholar
  31. 31.
    Simpson JA, Watkins ER, Price RN, Aarons L, Kyle DE, White NJ (2000) Mefloquine pharmacokinetic-pharmacodynamic models: implications for dosing and resistance. Antimicrob Agents Chemother 44:3414–3424PubMedCrossRefGoogle Scholar
  32. 32.
    Palmer KJ, Holliday SM, Brogden RN (1993) Mefloquine: a review of its antimalarial activity, pharmacokinetic properties and therapeutic efficacy. Drugs 45:430–475PubMedCrossRefGoogle Scholar
  33. 33.
    Ashley EA, McGready R, Hutagalung R, Phaiphun L, Slight T, Proux S, Thwai KL, Barends M, Looareesuwan S, White NJ et al (2005) A randomized, controlled study of a simple, once-daily regimen of dihydroartemisinin-piperaquine for the treatment of uncomplicated, multidrug-resistant falciparum malaria. Clin Infect Dis 41:425–432PubMedCrossRefGoogle Scholar
  34. 34.
    Bem JL, Kerr L, Stuerchler D (1992) Mefloquine prophylaxis: an overview of spontaneous reports of severe psychiatric reactions and convulsions. J Trop Med Hyg 95:167–179PubMedGoogle Scholar
  35. 35.
    Phillips-Howard PA, ter Kuile FO (1995) CNS adverse events associated with antimalarial agents. Fact or fiction? Drug Saf 12:370–383PubMedCrossRefGoogle Scholar
  36. 36.
    WHO (1991) Review of central nervous system adverse events related to the antimalarial drug, mefloquine (1985–1990). World Health Organization, GenevaGoogle Scholar
  37. 37.
    Schlagenhauf P, Steffen R, Lobel H, Johnson R, Letz R, Tschopp A, Vranjes N, Bergqvist Y, Ericsson O, Hellgren U et al (1996) Mefloquine tolerability during chemoprophylaxis: focus on adverse event assessments, stereochemistry and compliance. Trop Med Int Health 1:485–494PubMedCrossRefGoogle Scholar
  38. 38.
    Roche Laboratories Inc (2008) Lariam® (mefloquine hydrochloride) Complete Product Information. US Package Insert, Nutley, NJGoogle Scholar
  39. 39.
    Nevin RL, Pietrusiak PP, Caci JB (2008) Prevalence of contraindications to mefloquine use among USA military personnel deployed to Afghanistan. Malar J 7:30PubMedCrossRefGoogle Scholar
  40. 40.
    Hill DR (1991) Pre-travel health, immunization status, and demographics of travel to the developing world for individuals visiting a travel medicine service. Am J Trop Med Hyg 45:263–270PubMedGoogle Scholar
  41. 41.
    Nevin RL (2009) Epileptogenic potential of mefloquine chemoprophylaxis: a pathogenic hypothesis. Malar J 8:188PubMedCrossRefGoogle Scholar
  42. 42.
    Taylor WR, White NJ (2004) Antimalarial drug toxicity: a review. Drug Saf 27:25–61PubMedCrossRefGoogle Scholar
  43. 43.
    Baird JK (2005) Effectiveness of antimalarial drugs. N Engl J Med 352:1565–1577PubMedCrossRefGoogle Scholar
  44. 44.
    Weinke T, Trautmann M, Held T, Weber G, Eichenlaub D, Fleischer K, Kern W, Pohle HD (1991) Neuropsychiatric side effects after the use of mefloquine. Am J Trop Med Hyg 45:86–91PubMedGoogle Scholar
  45. 45.
    Luxemburger C, Nosten F, ter Kuiile F, Frejacques L, Chongsuphajaisiddhi T, White NJ (1991) Mefloquine for multidrug-resistant malaria. Lancet 338:1268PubMedCrossRefGoogle Scholar
  46. 46.
    Nguyen TH, Day NP, Ly VC, Waller D, Mai NT, Bethell DB, Tran TH, White NJ (1996) Post-malaria neurological syndrome. Lancet 348:917–921PubMedCrossRefGoogle Scholar
  47. 47.
    Pham YT, Nosten F, Farinotti R, White NJ, Gimenez F (1999) Cerebral uptake of mefloquine enantiomers in fatal cerebral malaria. Int J Clin Pharmacol Ther 37:58–61PubMedGoogle Scholar
  48. 48.
    Gimenez F, Gillotin C, Basco LK, Bouchaud O, Aubry AF, Wainer IW, Le Bras J, Farinotti R (1994) Plasma concentrations of the enantiomers of halofantrine and its main metabolite in malaria patients. Eur J Clin Pharmacol 46:561–562PubMedCrossRefGoogle Scholar
  49. 49.
    Pham YT, Regina A, Farinotti R, Couraud P, Wainer IW, Roux F, Gimenez F (2000) Interactions of racemic mefloquine and its enantiomers with P-glycoprotein in an immortalised rat brain capillary endothelial cell line, GPNT. Biochim Biophys Acta 1524:212–219PubMedCrossRefGoogle Scholar
  50. 50.
    Toovey S (2009) Mefloquine neurotoxicity: a literature review. Travel Med Infect Dis 7:2–6PubMedCrossRefGoogle Scholar
  51. 51.
    Milner E, McCalmont W, Bhonsle J, Caridha D, Carroll D, Gardner S, Gerena L, Gettayacamin M, Lanteri C, Luong T et al (2010) Structure-activity relationships amongst 4-position quinoline methanol antimalarials that inhibit the growth of drug sensitive and resistant strains of Plasmodium falciparum. Bioorg Med Chem Lett 20:1347–1351PubMedCrossRefGoogle Scholar
  52. 52.
    Milner E, McCalmont W, Bhonsle J, Caridha D, Cobar J, Gardner S, Gerena L, Goodine D, Lanteri C, Melendez V et al (2010) Anti-malarial activity of a non-piperidine library of next-generation quinoline methanols. Malar J 9:51PubMedCrossRefGoogle Scholar
  53. 53.
    Weiss SM, Benwell K, Cliffe IA, Gillespie RJ, Knight AR, Lerpiniere J, Misra A, Pratt RM, Revell D, Upton R et al (2003) Discovery of nonxanthine adenosine A2A receptor antagonists for the treatment of Parkinson’s disease. Neurology 61:S101–S106PubMedCrossRefGoogle Scholar
  54. 54.
    Gillespie RJ, Adams DR, Bebbington D, Benwell K, Cliffe IA, Dawson CE, Dourish CT, Fletcher A, Gaur S, Giles PR et al (2008) Antagonists of the human adenosine A2A receptor. Part 1: Discovery and synthesis of thieno[3,2-d]pyrimidine-4-methanone derivatives. Bioorg Med Chem Lett 18:2916–2919PubMedCrossRefGoogle Scholar
  55. 55.
    Gofton TE, Al-Khotani A, O’Farrell B, Ang LC, McLachlan RS (2011) Mefloquine in the treatment of progressive multifocal leukoencephalopathy. J Neurol Neurosurg Psychiatry 82:452–455PubMedCrossRefGoogle Scholar
  56. 56.
    Brickelmaier M, Lugovskoy A, Kartikeyan R, Reviriego-Mendoza MM, Allaire N, Simon K, Frisque RJ, Gorelik L (2009) Identification and characterization of mefloquine efficacy against JC virus in vitro. Antimicrob Agents Chemother 53:1840–1849PubMedCrossRefGoogle Scholar
  57. 57.
    Keiser J, Utzinger J (2010) The drugs we have and the drugs we need against major helminth infections. Adv Parasitol 73:197–230PubMedCrossRefGoogle Scholar
  58. 58.
    Holtfreter MC, Loebermann M, Klammt S, Sombetzki M, Bodammer P, Riebold D, Kinzelbach R, Reisinger EC (2011) Schistosoma mansoni: schistosomicidal effect of mefloquine and primaquine in vitro. Exp Parasitol 127:270–276PubMedCrossRefGoogle Scholar
  59. 59.
    Xiao SH, Xue J, Li-Li X, Zhang YN, Qiang HQ (2010) Effectiveness of mefloquine against Clonorchis sinensis in rats and Paragonimus westermani in dogs. Parasitol Res 107:1391–1397PubMedCrossRefGoogle Scholar
  60. 60.
    Auparakkitanon S, Chapoomram S, Kuaha K, Chirachariyavej T, Wilairat P (2006) Targeting of hematin by the antimalarial pyronaridine. Antimicrob Agents Chemother 50:2197–2200PubMedCrossRefGoogle Scholar
  61. 61.
    Chavalitshewinkoon-Petmitr P, Pongvilairat G, Auparakkitanon S, Wilairat P (2000) Gametocytocidal activity of pyronaridine and DNA topoisomerase II inhibitors against multidrug-resistant Plasmodium falciparum in vitro. Parasitol Int 48:275–280PubMedCrossRefGoogle Scholar
  62. 62.
    Tshefu AK, Gaye O, Kayentao K, Thompson R, Bhatt KM, Sesay SS, Bustos DG, Tjitra E, Bedu-Addo G, Borghini-Fuhrer I et al (2010) Efficacy and safety of a fixed-dose oral combination of pyronaridine-artesunate compared with artemether-lumefantrine in children and adults with uncomplicated Plasmodium falciparum malaria: a randomised non-inferiority trial. Lancet 375:1457–1467PubMedCrossRefGoogle Scholar
  63. 63.
    Park SH, Pradeep K (2010) Absorption, distribution, excretion, and pharmacokinetics of 14 C-pyronaridine tetraphosphate in male and female Sprague-Dawley rats. J Biomed Biotechnol 2010:590707PubMedGoogle Scholar
  64. 64.
    Wattanavijitkul T. (2010) Population pharmacokinetics of pyronaridine in the treatment of malaria. Ph.D. dissertation, University of Iowa. Accessed 15 Apr 2011
  65. 65.
    Looareesuwan S, Kyle DE, Viravan C, Vanijanonta S, Wilairatana P, Wernsdorfer WH (1996) Clinical study of pyronaridine for the treatment of acute uncomplicated falciparum malaria in Thailand. Am J Trop Med Hyg 54:205–209PubMedGoogle Scholar
  66. 66.
    Elueze EI, Croft SL, Warhurst DC (1996) Activity of pyronaridine and mepacrine against twelve strains of Plasmodium falciparum in vitro. J Antimicrob Chemother 37:511–518PubMedCrossRefGoogle Scholar
  67. 67.
    de Villiers KA, Marques HM, Egan TJ (2008) The crystal structure of halofantrine-ferriprotoporphyrin IX and the mechanism of action of arylmethanol antimalarials. J Inorg Biochem 102:1660–1667PubMedCrossRefGoogle Scholar
  68. 68.
    Sanchez CP, Rotmann A, Stein WD, Lanzer M (2008) Polymorphisms within PfMDR1 alter the substrate specificity for anti-malarial drugs in Plasmodium falciparum. Mol Microbiol 70:786–798PubMedGoogle Scholar
  69. 69.
    ter Kuile FO, Dolan G, Nosten F, Edstein MD, Luxemburger C, Phaipun L, Chongsuphajaisiddhi T, Webster HK, White NJ (1993) Halofantrine versus mefloquine in treatment of multidrug-resistant falciparum malaria [see comments]. Lancet 341:1044–1049PubMedCrossRefGoogle Scholar
  70. 70.
    Nosten F, ter Kuile F, Luxemburger C, Woodrow C, Kyle DE, Chongsuphajaisiddhi T, White NJ (1993) Cardiac effects of antimalarial treatment with halofantrine. Lancet 341:1054–1056PubMedCrossRefGoogle Scholar
  71. 71.
    Ashley EA, Stepniewska K, Lindegardh N, Annerberg A, Kham A, Brockman A, Singhasivanon P, White NJ, Nosten F (2007) How much fat is necessary to optimize lumefantrine oral bioavailability? Trop Med Int Health 12:195–200PubMedCrossRefGoogle Scholar
  72. 72.
    Tie H, Walker BD, Singleton CB, Valenzuela SM, Bursill JA, Wyse KR, Breit SN, Campbell TJ (2000) Inhibition of HERG potassium channels by the antimalarial agent halofantrine. Br J Pharmacol 130:1967–1975PubMedCrossRefGoogle Scholar
  73. 73.
    Warhurst DC, Craig JC, Adagu IS, Guy RK, Madrid PB, Fivelman QL (2007) Activity of piperaquine and other 4-aminoquinoline antiplasmodial drugs against chloroquine-sensitive and resistant blood-stages of Plasmodium falciparum. Role of beta-haematin inhibition and drug concentration in vacuolar water- and lipid-phases. Biochem Pharmacol 73:1910–1926PubMedCrossRefGoogle Scholar
  74. 74.
    Tarning J, Lindegardh N, Annerberg A, Singtoroj T, Day NP, Ashton M, White NJ (2005) Pitfalls in estimating piperaquine elimination. Antimicrob Agents Chemother 49:5127–5128PubMedCrossRefGoogle Scholar
  75. 75.
    Tarning J, Ashley EA, Lindegardh N, Stepniewska K, Phaiphun L, Day NP, McGready R, Ashton M, Nosten F, White NJ (2008) Population pharmacokinetics of piperaquine after two different treatment regimens with dihydroartemisinin-piperaquine in patients with Plasmodium falciparum malaria in Thailand. Antimicrob Agents Chemother 52:1052–1061PubMedCrossRefGoogle Scholar
  76. 76.
    Briolant S, Henry M, Oeuvray C, Amalvict R, Baret E, Didillon E, Rogier C, Pradines B (2010) Absence of association between piperaquine in vitro responses and polymorphisms in the pfcrt, pfmdr1, pfmrp, and pfnhe genes in Plasmodium falciparum. Antimicrob Agents Chemother 54:3537–3544PubMedCrossRefGoogle Scholar
  77. 77.
    Muangnoicharoen S, Johnson DJ, Looareesuwan S, Krudsood S, Ward SA (2009) Role of known molecular markers of resistance in the antimalarial potency of piperaquine and dihydroartemisinin in vitro. Antimicrob Agents Chemother 53:1362–1366PubMedCrossRefGoogle Scholar
  78. 78.
    Ashley EA, Stepniewska K, Lindegardh N, McGready R, Annerberg A, Hutagalung R, Singtoroj T, Hla G, Brockman A, Proux S et al (2007) Pharmacokinetic study of artemether-lumefantrine given once daily for the treatment of uncomplicated multidrug-resistant falciparum malaria. Trop Med Int Health 12:201–208PubMedCrossRefGoogle Scholar
  79. 79.
    van Vugt M, Wilairatana P, Gemperli B, Gathmann I, Phaipun L, Brockman A, Luxemburger C, White NJ, Nosten F, Looareesuwan S (1999) Efficacy of six doses of artemether-lumefantrine (benflumetol) in multidrug-resistant Plasmodium falciparum malaria. Am J Trop Med Hyg 60:936–942PubMedGoogle Scholar
  80. 80.
    Price RN, Uhlemann AC, van Vugt M, Brockman A, Hutagalung R, Nair S, Nash D, Singhasivanon P, Anderson TJ, Krishna S et al (2006) Molecular and pharmacological determinants of the therapeutic response to artemether-lumefantrine in multidrug-resistant Plasmodium falciparum malaria. Clin Infect Dis 42:1570–1577PubMedCrossRefGoogle Scholar
  81. 81.
    White NJ, van Vugt M, Ezzet F (1999) Clinical pharmacokinetics and pharmacodynamics and pharmacodynamics of artemether-lumefantrine. Clin Pharmacokinet 37:105–125PubMedCrossRefGoogle Scholar
  82. 82.
    McGready R, Tan SO, Ashley EA, Pimanpanarak M, Viladpai-Nguen J, Phaiphun L, Wustefeld K, Barends M, Laochan N, Keereecharoen L et al (2008) A randomised controlled trial of artemether-lumefantrine versus artesunate for uncomplicated Plasmodium falciparum treatment in pregnancy. PLoS Med 5:e253PubMedCrossRefGoogle Scholar
  83. 83.
    Anderson TJ, Nair S, Qin H, Singlam S, Brockman A, Paiphun L, Nosten F (2005) Are transporter genes other than the chloroquine resistance locus (pfcrt) and multidrug resistance gene (pfmdr) associated with antimalarial drug resistance? Antimicrob Agents Chemother 49:2180–2188PubMedCrossRefGoogle Scholar
  84. 84.
    Johnson DJ, Fidock DA, Mungthin M, Lakshmanan V, Sidhu AB, Bray PG, Ward SA (2004) Evidence for a central role for PfCRT in conferring Plasmodium falciparum resistance to diverse antimalarial agents. Mol Cell 15:867–877PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel AG 2011

Authors and Affiliations

  • Francois Nosten
    • 1
    • 2
    • 3
    Email author
  • Penelope A. Phillips-Howard
    • 4
  • Feiko O. ter Kuile
    • 5
  1. 1.Nuffield Department of Clinical Medicine, Centre for Tropical Medicine, Churchill HospitalUniversity of OxfordOxfordUK
  2. 2.Shoklo Malaria Research UnitMae SotThailand
  3. 3.Mahidol UniversityBangkokThailand
  4. 4.Centre for Public HealthLiverpool John Moores UniversityLiverpoolUK
  5. 5.Malaria Epidemiology Unit Child and Reproductive Health GroupLiverpool School of Tropical MedicineLiverpoolUK

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